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Purpose@#Osteosarcoma (OS) universally exhibits heterogeneity and cisplatin (CDDP) resistance. Although the Wee1/CDC2 and nuclear factor кB (NF-κB) pathways were reported to show abnormal activation in some tumor cells with CDDP resistance, whether there is any concrete connection is currently unclear. We explored it in human OS cells. @*Materials and Methods@#Multiple OS cell lines were exposed to a Wee1 inhibitor (AZD1775) and CDDP to assess the half-maximal inhibitory concentration values. Western blot, coimmunoprecipitation, confocal immunofluorescence, cell cycle, and Cell Counting Kit-8assays were performed to explore the connection between the Wee1/CDC2 and NF-κB pathways and their subsequent physiological contribution to CDDP resistance. Finally, CDDP-resistant PDX-OS xenograft models were established to confirm that AZD1775 restores the antitumor effects of CDDP. @*Results@#A sensitivity hierarchy of OS cells to CDDP and AZD1775 exists. In the highly CDDP-tolerant cell lines, Wee1 and RelA were physically crosslinked, which resulted in increased abundance of phosphorylated CDC2 (Y15) and RelA (S536) and consequent modulation of cell cycle progression, survival, and proliferation. Wee1 inhibition restored the effects of CDDP on these processes in CDDP-resistant OS cells. In addition, animal experiments with CDDP-resistant PDX-OS cells showed that AZD1775 combined with CDDP not only restored CDDP efficacy but also amplified AZD1775 in inhibiting tumor growth and prolonged the median survival of the mice. @*Conclusion@#Simultaneous enrichment of molecules in the Wee1/CDC2 and NF-κB pathways and their consequent coactivation is a new molecular mechanism of CDDP resistance in OS cells. OS with this molecular signature may respond well to Wee1 inhibition as an alternative treatment strategy.
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Objective:To investigate the reparative efficacy and mechanism of pressure-adjustable macroporous antibacterial hydrogel in the treatment of infected wounds.Methods:Staphylococcus aureus was used to establish wound infection models in healthy C57BL/6 mice. The models were divided into 3 groups subjected to 3 different treatments: a negative control group with no hydrogel treatment (group A), a control group treated by common medical hydrogel (group B) and an experiment group treated by pressure-adjustable macroporous antibacterial hydrogel (group C). On days 1, 3, 6, 9 and 12, the effects of 3 treatments were compared on the wound area and the number of bacterial colonies under scab, on the apoptosis of fibroblasts based on the changes of type Ⅰ procollagen, and on the inhibition of inflammation during wound repair by detecting the expression of interleukin-6 (IL-6) and tumor necrosis factor (TNF-α).Results:On days 1 and 3, there was no significant difference between the 3 groups in the wound area ( P>0.05), but on days 6, 9 and 12, there were significant differences between the 3 groups in the wound area ( P<0.05). On day 6, the wound areas in group B (1.23 cm 2 ± 0.16 cm 2) and in group C (1.14 cm 2 ± 0.12 cm 2) were significantly smaller than that in group A (1.56 cm 2 ± 0.16 cm 2) ( P<0.05), but there was no significant difference between groups B and C ( P>0.05). On days 9 and 12, the wound areas in group B (0.97 cm 2 ± 0.13 cm 2 and 0.76 cm 2 ± 0.10 cm 2) and in group C (0.66 cm 2 ± 0.06 cm 2 and 0.48 cm 2 ± 0.07 cm 2) were significantly smaller than those in group A (1.49 cm 2 ± 0.11 cm 2 and 1.39 cm 2 ± 0.13 cm 2), and those in group C were significantly smaller than those in group B (all P<0.05). On day 1, there was no significant difference between the 3 groups in the number of bacterial colonies under scab ( P>0.05). On days 3, 6, 9 and 12, the numbers of bacterial colonies under scab in groups B and C were significantly smaller than that in group A ( P<0.05), and that in group C was significantly smaller than that in group B ( P< 0.05). The nucleic acid electrophoresis showed that the grayscale bands in group C were significantly darker than those in groups A and B. The early apoptosis rate of the fibroblasts in group C[low-right positive fluorescence (LR%): 9.72%] was significantly lower than that in group A (43.99%) and that in group B (38.43%), and that in group B was significantly lower than that in group A ( P<0.05). On day 12, the ratio of the gray values of IL-6 and β-actin (0.64 ± 0.10) and the ratio of the gray values of TNF-α and β-actin (0.34 ± 0.05) in the fibroblasts in group C were significantly higher than those in group A (1.22 ± 0.21 and 0.60 ± 0.14) and in group B (0.88 ± 0.02 and 0.41 ± 0.06) ( P<0.01). Conclusion:The pressure-adjustable macroporous antibacterial hydrogel is an effective treatment of infected wounds and its mechanism may be related to the reduced apoptosis of fibroblasts.
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BACKGROUND:Vertebroplasty and kyphoplasty can effectively repair osteoporotic vertebral compression fractures, but bone cement injection can cause the change of stress in the fractured vertebrae and adjacent vertebrae after surgery, leading to new fractures. OBJECTIVE: To analyze the stress changes of the fractured vertebrae and adjacent vertebrae after vertebroplasty with different elastic modulus bone cement by a three-dimensional finite element method. METHODS: One healthy adult male volunteer was selected for lumbar spine CT scan. The acquired images were imported for three-dimensional reconstruction using Mimics. The three-dimensional model was smoothed, polished and denoised by Geomagic software, and then the solid mode was built under Workbench Ansys. An osteoporotic vertebral compression fracture model in L2-4 segments was established after assignment. Bone cement (4 mL) with different elastic moduli (8 000, 4 000, 2 000 and 1 000 MPa) injected into the L3 segment distributed in the middle of the vertebrae as spherical shape. 500 N pre-load was applied on the L2 surface with an additional bending moment of 50 N?m. The lower surface free degree of L4 was restrained. The L2-4 forward flexion, posterior extension, right flexion and axial rotation on the right side were stimulated. The stress changes of the fractured vertebrae and the upper and lower adjacent vertebrae before and after bone cement injection with different elastic moduli were compared. RESULTS AND CONCLUSION:The stress of the fractured vertebrae and adjacent vertebrae were significantly increased compared with that before operation. With the increase of elastic modulus, the stress of the fractured vertebrae increased, but there were no changes in the stress of adjacent vertebrae. These findings indicate that the elastic modulus of bone cement may be a method to reduce new fractures of the fractured and adjacent vertebrae after bone cement injection.
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BACKGROUND:Vertebroplasty and kyphoplasty can effectively repair osteoporotic vertebral compression fractures, but postoperative change of stress in the fractured vertebrae and adjacent vertebrae can lead to new fractures. OBJECTIVE:To analyze the stress changes of the fractured and adjacent vertebrae with different bone cement injection volume by three-dimensional finite element method. METHODS:One healthy adult male volunteer was selected for lumbar spine CT scan. The acquired images were imported for three-dimensional reconstruction using Mimics. The three-dimensional model was smoothed, polished and denoised by Geomagic software, and then the solid mode was built under Workbench Ansys. The osteoporotic vertebral compression fracture model in L2-L4 segments was established after assignment. Bone cement of 1, 2, 4, 6 mL was injected into the L3 vertebrae respectively and distributed in the middle of the vertebrae as spherical shape. 500 N pre-load was applied on L2 surface with an additional moment of 50 N·m. The lower surface free degree of L4 was restrainted. The L2-L4 forward flexion, extension, right flexion and axial rotation on the right side were stimulated to compare the stress changes of fractured vertebrae and adjacent vertebrae before and after the bone cement injection with different volume. RESULTS AND CONCLUSION:The stresses of fractured and adjacent vertebrae after the bone cement injection were significantly increased; meanwhile, the stresses of fractured and adjacent vertebrae increased with the increase of bone cement injection volume, which may be one of the factors leading to the compression fractures of adjacent vertebrae.
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BACKGROUND:Percutaneous vertebroplasty and kyphoplasty are both effective in the treatment of osteoporotic vertebral compression fractures, but different in the distribution and dispersion of bone cement. ＜br> OBJECTIVE:To analyze the factors affecting the bone cement dispersion within the vertebral body in treatment of osteoporotic vertebral compression fracture with vertebroplasty or kyphoplasty. ＜br> METHODS:A total of 41 patients with osteoporotic vertebral compression fractures were included, and divided into three groups:group A (22 cases receiving high viscosity bone cement vertebroplasty treatment), group B (5 cases receiving high viscosity bone cement kyphoplasty), group C (14 cases receiving low viscosity bone cement vertebroplasty treatment). The groups A and C were divided into subgroups according to bone cement injection volume, time from fracture to operation, preoperative degree of vertebral compression. The distribution and dispersion of bone cement in the vertebra were reconstructed by the CT three-dimensional imaging and volume rendering analysis. ＜br> RESULTS AND CONCLUSION:In the three groups, after operation, relative dispersion area and relative dispersion volume in the vertebrae had no obvious difference, and the bone cement could al diffuse to upper and lower lamina cross the vertebral midline. There was no significant difference in bone cement diffusion coefficient among the three groups. In a certain range, the bone cement injection volume and bone cement dispersion volume was positively correlated. In groups A and C, bone cement diffusion coefficient decreased with the increasing of bone cement injection volume, time from fracture to operation, and the compression degree of the fractured vertebrae, but showed no significant correlation with bone cement viscosity.